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Fulvestrant is a drug treatment of hormone receptor-positive metastatic breast cancer in post-menopausal women with disease progression following anti-estrogen therapy. It is an estrogen receptor antagonist with no agonist effects, which works both by down-regulating and by degrading the estrogen receptor.

Fulvestrant is a selective estrogen receptor down-regulator (SERD). Fulvestrant is indicated for the treatment of hormone receptor positive metastatic breast cancer in postmenopausal women with disease progression following anti-estrogen therapy. The dosing schedule for fulvestrant remains under investigation in an attempt to optimize its effectiveness.[2]

Clinical trials

Metastatic or locally advanced breast cancer

Fulvestrant provided effective second-line therapy in this setting for postmenopausal women who had relapsed or progressed after previous endocrine therapy.[3]

In particular 4 clinical trials in this setting did show similar efficacy to the other hormonal agents (aromatase inhibitors and tamoxifen) with good tolerability profile. Fulvestrant had a lower incidence of joint disorders.[4][5]

Patent extension

The original patent for Faslodex expired in October 2004. Drugs subject to pre-marketing regulatory review are eligible for patent extension, and for this reason AstraZeneca got an extension of the patent to December 2011.[9][10]

AstraZeneca has filed later patents. There is no generic Faslodex available.[11] A later patent for Faslodex expires in January 2021.[12]

FASLODEX® (fulvestrant) injection for intramuscular administration is an estrogen receptor antagonist. The chemical name is 7-alpha-[9-(4,4,5,5,5-penta fluoropentylsulphinyl) nonyl]estra-1,3,5-(10)- triene-3,17beta-diol. The molecular formula is C32H47F5O3S and its structural formula is:

Fulvestrant is a white powder with a molecular weight of 606.77. The solution for injection is a clear, colorless to yellow, viscous liquid.

Each injection contains as inactive ingredients: 10% w/v Alcohol, USP, 10% w/v Benzyl Alcohol, NF, and 15% w/v Benzyl Benzoate, USP, as co-solvents, and made up to 100% w/v with Castor Oil, USP as a co-solvent and release rate modifier.

Fulvestrant is a pure antiestrogen that represent a significant breakthrough in the treatment of breast cancer. Despite its pure antagonist activity, studies on ovariectomized rats have confirmed that fulvestrant, in contrast to Tamoxifen which acts like estrogen to reduce periosteal bone formation, does not alter estrogen-like or antiestrogenic effects. Fulvestrant also has some distinct advantages on target organs other than breast tissue.

Fulvestrant is a steroidal pure antiestrogen with a chemical structure similar to estradiol. Studies of etrogen receptor (ER) function have demonstrated that estradiol binding to the ER initiate a sequence of events. Fulvestrant antagonizes estrogen action by occupying the ER and preventing estrogen-stimulated gene activation, thus interfering with the estrogen related processes essential for cell-cycle competion.

Fulvestrant, 7-alpha- [9-(4,4,5,5,5pentafluoropentylsulphinyl) nonyl]-estra-1,3,5 (10)-triene-3,17β-diol, has the following formula:

WO Patent application No. 02/32922 describes a process for preparing an intermediate compound useful for preparing, e.g. fulvestrant, which process comprises aromatization of a compoud, and thereafter if necessary or desired, carrying out one or more of the following steps: (i) removing any hydroxy protecting group; (ii) converting a precursor group to a different such group.

EP Patent No. 0138504 relates to certain 7α-substituted derivatives of oestradiol and related steroids which possess antioestrogenic activity. US Patent No. 4659516 , EP Patent No. 0138504 and Bowler, Steroids 1989, 54, 71 describe a process for making steroids such as fulvestrant, by which 1,6-conjugate addition of an alkyl group to an estra-4,6-diene-3-one gave a ratio of 7α- to 7β-epimer of 1.2 : 1 (isolated). In WO 02/32922 it is stated that the ratio of epimers obtained using this process on an industrial scale is 1.9: 1.

A solution of 40.5 grams of Cp 9363 in 320 grams tetrahydrofuran and 81 grams methanol was cooled to 5°C and treated with a warm solution of 27 grams sodium (meta) periodate in 183 grams water. The mixture was allowed to stand at room temperature overnight, concentrated under vacuum and then dissolved in dichloromethane, extracted with water and evaporated to give 40 grams of Cp 9368 (fulvestrant 17-acetate).

The oily residue of Cp 9368 (40 grams) was dissolved in 320 grams of methanol under nitrogen and treated for 3 hours at room temperature with a solution of 20 grams of potassium hydroxide in 128 grams methanol. After neutralisation with 30 grams of acetic acid, the reaction mixture was concentrated under vacuum and then dissolved in dichloromethane, extracted with water and evaporated. The oily residue was crystallised from 400 grams of toluene, then dried under vacuum to constant weight. 26.6 grams of fulvestrant were obtained.

A solution of 41 grams of Cp 9304 in 328 grams tetrahydrofuran and 82 grams methanol was cooled to 5°C and treated with a warm solution of 27 grams sodium (meta)periodate in 185 grams water. The mixture was allowed to stand at room temperature overnight, concentrated under vacuum and then dissolved in dichloromethane, extracted with water, evaporated, and crystallised from toluene to give 28 grams of Cp 9305 (fulvestrant). Further purification can be effected by recrystallisation from ethyl acetate.

The development of a commercial manufacturing process for fulvestrant (the active ingredient in ‘Faslodex’) is described. Key steps in the synthesis are stereoselective 1,6-addition of an organocuprate to a steroidal dienone followed by copper-mediated aromatisation of the A-ring. The strategy for dealing with noncrystalline intermediates is outlined. The production of drug substance of acceptable quality is critically dependent on limiting the formation of key impurities. The origin of these impurities is discussed, and measures to prevent or control their formation are described.

An approximately 50% w/w solution of 26 (assumed content 308 kg, 521 mol as a mixture of 7α- and 7β-isomers) in EtOAc was diluted with more EtOAc (695 kg) and glacial acetic acid (188 kg, 3131 mol). Aqueous hydrogen peroxide (17.5% w/v, 203 kg, 1045 mol) was added, ………………….DELETED………….. to another crystallisation cycle. In total, four crystallisations were carried out to achieve the required purity (<0.1% 7β-isomer). With each successive crystallisation, the EtOAc solution was concentrated to a predetermined volume that decreased in proportion to the estimated weight of product present (based on laboratory experiments and HPLC analysis). After the final crystallisation the product was dried in a stream of nitrogen at 60 °C. The yield of pure fulvestrant at 100% w/w strength was 88.4 kg (mean of five batches) which represents 28% overall yield from dienone 2. Ratio of sulfoxide A to sulfoxide B = 46:54 by HPLC analysis (the retention times of sulfoxide A and sulfoxide B are approximately 20.0 and 23.5 min); mp 104−112 °C by DSC analysis (sulfoxide A and sulfoxide B have mp 102 and 117 °C).

Process for the preparation of fulvestrant and its intermediates. Appears to be the first filing from Intas Pharmaceuticals on this API. Family members of the product patent, WO0151056 (assigned to AstraZeneca), expire in the EU states and in the US in 2021

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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international,
etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules
and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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